Neolignans from Aristolochia fordiana Prevent Oxidative Stress-Induced Neuronal Death through Maintaining the Nrf2/HO-1 Pathway in HT22 Cells

Bioassay-guided fractionation of the ethanolic extract of the stems of Aristolochia fordiana led to the isolation of six new dihydrobenzofuran neolignans (1-3 and 7-9), three new 2-aryldihydrobenzofurans (4-6), a new 8-O-4' neolignan (10), and 14 known analogues (11-24). The structures of compounds 1-10 were established by spectroscopic methods, and their absolute configurations were determined by analyses of the specific rotation and electronic circular dichroism data. The neuroprotective effects of compounds 1-24 against glutamate-induced cell death were tested in hippocampal neuronal cell line HT22. Compounds 17 and 20-24 exhibited moderate neuroprotective activity by increasing the endogenous antioxidant defense system. In addition, the neolignans activated the Nrf2 (nuclear factor E2-related factor 2) pathway, resulting in the increase of the expression of endogenous antioxidant protein HO-1 (heme oxygenase-1). The active compounds also preserved the levels of antiapoptotic protein Bcl-2 (B cell lymphoma/leukemia-2), which was decreased by glutamate. Collectively, these results suggested that the active neolignans protect neurons against glutamate-induced cell death through maintaining the Nrf2/HO-1 signaling pathway as well as preserving the Bcl-2 protein and might be promising novel beneficial agents for oxidative stress-associated diseases.